Stem Cell Transplantation Extends the Reproductive Lifespan of Naturally Aging Cynomolgus Monkeys

Background of the Study

The ovary is a crucial organ for female reproduction and health, responsible for producing oocytes and secreting sex hormones. As women age, ovarian reserves gradually decline, eventually leading to menopause, which brings about various health issues such as osteoporosis, cardiovascular diseases, and neurodegenerative disorders. Although hormone replacement therapy (HRT) is often used to alleviate menopausal symptoms, its long-term use may pose several health risks, such as increased risks of coronary heart disease, invasive breast cancer, and stroke. Therefore, scientists are seeking a safe and effective alternative to delay the natural aging of ovaries.

In recent years, mesenchymal stem cell (MSC) therapy has shown some success in restoring ovarian function in animal models and women with premature ovarian insufficiency. However, existing studies mainly focus on treating early-stage ovarian dysfunction, and there is still a lack of research on whether MSC transplantation can benefit the naturally aging ovary. In addition, obtaining MSCs from donors could be limited by their availability and heterogeneity. Therefore, this study introduced a novel type of stem cell—mesenchymal stem cell-like cells (M cells) derived from human embryonic stem cells—and tested their efficacy and mechanism in delaying ovarian aging using a naturally aging cynomolgus monkey (Macaca fascicularis) model.

Source of the Research

The research was conducted by a team led by Yan Long, Wan Tu, and others, who belong to several Chinese research institutions, including the Chinese Academy of Sciences. The paper was published in 2024 in the journal Cell Discovery, providing the latest findings on the potential of stem cell transplantation to delay ovarian aging.

Research Process

Analysis of Ovarian Reserve in Chinese Women

To better understand the ovarian reserve status of Chinese women, the research team conducted a quantitative morphometric study on 28 ovarian samples from 26 Chinese women aged between 35 and 52 years. The samples were sliced using systematic random sampling, stained, and scanned to count the number of follicles in the ovaries. The results showed a significant decline in primordial follicles with age. However, some primordial follicles were still retained in the perimenopausal ovaries, demonstrating potential developmental activity. Moreover, the study found that the degree of ovarian fibrosis increased significantly with age, indicating the deterioration of the ovarian microenvironment.

M Cell Transplantation Experiment

The research team selected ten cynomolgus monkeys, aged between 18 and 23 years, which were in the perimenopausal phase, displaying characteristics such as irregular menstruation, reduced ovarian volume, and lower levels of sex hormones. The monkeys were divided into a treated group (seven monkeys) and a control group (three monkeys), and M cells or saline were injected into the bilateral ovaries, respectively. This was followed by an eight-month follow-up, during which the health status, ovarian and uterine morphology, sex hormone levels, and reproductive capabilities of the monkeys were monitored.

During the transplantation experiment, the team observed changes in ovarian and uterine morphology, endometrial thickness, and estrogen and progesterone levels using ultrasound and biochemical analysis. The results indicated that M cell transplantation significantly increased ovarian diameter and endometrial thickness while also boosting sex hormone secretion levels. Six months after transplantation, serum estrogen levels in the treated group were significantly higher than those in the control group, and progesterone levels remained elevated in most treated monkeys.

Extending Reproductive Lifespan

To further evaluate the improvement in reproductive function, the research team assessed the fertility of the monkeys through superovulation and natural mating. The control group yielded no oocytes, while the treated group obtained a total of 51 oocytes, some of which were fertilized and developed into blastocysts. Moreover, one of the treated monkeys conceived and gave birth to a healthy baby monkey through natural mating, providing valuable support for the practical application of M cell transplantation.

Transcriptomic Analysis Reveals Molecular Mechanisms

To uncover the potential mechanisms by which M cell transplantation restores ovarian function, the research team conducted single-cell RNA sequencing (scRNA-seq) on ovarian tissues from the treated and control groups. The results showed that M cell transplantation promoted the proliferation of granulosa cells (GCs) and stromal cells while enhancing angiogenesis. Meanwhile, the degree of inflammation and fibrosis was significantly reduced in the ovarian tissue of the treated group, indicating an improvement in the ovarian microenvironment.

Further analysis revealed that genes such as PPARG, PRDX4, and RDX were significantly upregulated in GCs, which were related to anti-inflammatory, antioxidant, and proliferative activities. In stromal cells, upregulation of genes like PPARG, NFKB1, and HSF1 promoted wound healing and enhanced oxygen response. These changes in gene regulatory networks provided evidence for the molecular mechanisms through which M cell transplantation improves ovarian function.

In Vitro Validation

To validate the anti-aging effects of M cells in vitro, the team co-cultured senescent KGN cells (a granulosa cell tumor line) with M cells. The results demonstrated that M cells significantly reduced oxidative damage and apoptosis in senescent KGN cells and upregulated the expression of PPARG, PRDX4, and RDX, inhibiting the production of senescence markers and inflammatory factors. These findings indicated that M cells can modulate key factors in the ovarian microenvironment, delaying granulosa cell aging and improving ovarian function.

Research Conclusions

This study demonstrated the significant effect of M cells in delaying ovarian aging and extending the reproductive lifespan. Through transplantation experiments in naturally aging cynomolgus monkeys, the researchers showed that M cells could reduce ovarian fibrosis and inflammation, promote follicle development and sex hormone secretion, and successfully improve reproductive capacity. Furthermore, transcriptomic analysis and in vitro functional validation identified the importance of genes like PPARG, PRDX4, and RDX in improving the ovarian microenvironment.

Significance and Value of the Research

This research not only provides new directions for stem cell therapy but also brings hope for treating female reproductive aging. In the future, M cell transplantation may become an important strategy for delaying ovarian aging and improving menopausal health. Through this study, scientists gained valuable insights into the mechanisms of ovarian aging, especially the role of the cellular microenvironment in the aging process, laying a solid foundation for future clinical studies.

The successful use of M cell transplantation offers a promising clinical application to improve female reproductive health and extend reproductive lifespan, advancing the development of stem cell technologies.